What is Lesch-Nyhan syndrome?

Risk Factors

Males and individuals who have male family members on their mother’s side of the family with Lesch-Nyhan syndrome are at risk for developing the disorder.

Etiology and Genetics

Lesch-Nyhan syndrome results from a mutation in the HPRT1 gene, found on the long arm of the X chromosome at position Xq26.1. This gene encodes the enzyme hypoxanthine phosphoribosyltransferase 1, which is an essential enzyme in the purine salvage pathway. Proper functioning of this pathway allows cells to recycle purines, one of the building blocks of DNA and RNA, rather than having to synthesize them from scratch. In the absence of the HPRT1 enzyme, the pathway is blocked and there is an accumulation in the body of uric acid, a waste product of purine decomposition. Excess uric acid can cause arthritis, kidney stones, and bladder stones, yet it is unclear how the enzyme deficiency causes the behavioral and neurological problems associated with this disease.

Inheritance of Lesch-Nyhan syndrome follows a strict sex-linked recessive pattern. Only males are affected, and they inherit the defective gene from their mothers. Mothers who carry the mutated gene on one of their two X chromosomes are unaffected, but they face a 50 percent chance of transmitting this disorder to each of their male children. Female children have a 50 percent chance of inheriting the gene and becoming carriers like their mothers. Affected males rarely live to reproduce, but in that unlikely event they would pass the mutation on to all of their daughters but to none of their sons.

Symptoms

The first symptom of Lesch-Nyhan syndrome is an orange-colored crystal-like deposit in the diaper. This may occur in children as young as three months. These deposits are caused by increased uric acid in the urine.

Other symptoms include irritability and nervous system impairment. Symptoms of nervous system impairment for an infant who is from four to six months old include a lack of muscle tone and an inability to lift the head. Symptoms in infants who are six months old include an unusual arching of the back; symptoms in a nine-month-old child include the inability to crawl or stand. At twelve months, a child’s symptoms include an inability to walk. Symptoms in children who are older than twelve months include spasms of the limbs and facial muscles. Additional symptoms include kidney stones, blood in the urine, pain and swelling of joints, difficulty swallowing (dysphagia), impaired kidney function, self-injury, and uric acid deposits in the joints.

Self-mutilating behavior is the hallmark of this disease. Children begin to bite their fingers, their lips, and the insides of their mouths as early as two years old. As children grow, self-injury becomes increasingly compulsive and severe. Eventually, mechanical physical restraints will be necessary to prevent head and leg banging, nose gouging, loss of fingers and lips from biting, and loss of vision from eye rubbing, among other behaviors. In addition to self-injury, older children and teens will become physically and verbally aggressive.

The cause of these behaviors is not entirely understood. However, some experts believe they are related to abnormalities in brain chemicals called neurotransmitters. It should be stressed that these children do not want to hurt themselves or others, but they are incapable of preventing these behaviors. Individuals with Lesch-Nyhan syndrome have been described as “doing the opposite” of what they really want.

Screening and Diagnosis

The doctor will ask about symptoms, behavior traits, and medical history and will perform a physical exam. Tests may include a measurement of HPRT enzyme activity to confirm the diagnosis. Molecular genetic testing of the HPRT1 gene may be done to confirm the diagnosis and to detect if an unaffected female is a carrier of the gene mutation.

Treatment and Therapy

There is no treatment to cure Lesch-Nyhan. However, certain medications may help to alleviate some of its symptoms. For example, allopurinol (Aloprim, Zyloprim) may be prescribed to control excessive levels of uric acid in the body; diazepam (Diastat, Valium), haloperidol (Haldol), and phenobarbital (Luminal) can help reduce some of the problem behaviors.

A single 2006 report suggests that administration of s-adenosylmethionine, a food supplement, may reduce self-mutilating behaviors in adults with Lesch-Nyhan syndrome. This supplement, which is available in health food stores, is naturally synthesized by the human body and is important for many bodily processes. Patients should talk to their health care providers, however, before taking any supplements.

With treatment, the average life expectancy for Lesch-Nyhan patients is early to mid-twenties. There may be an increased risk of sudden death due to respiratory causes. However, many patients live longer with good medical and psychological care.

Prevention and Outcomes

There are no guidelines to prevent Lesch-Nyhan syndrome. Individuals with a a family history of this condition can talk to a genetic counselor when deciding whether to have children.

Bibliography

EBSCO Publishing. Health Library: Lesch-Nyhan Syndrome. Ipswich, Mass.: Author, 2009. Available through http://www.ebscohost.com.

Glick, N. “Dramatic Reduction in Self-Injury in Lesch-Nyhan Disease Following S-Adenosylmethionine Administration.” Journal of Inherited Metabolic Disease 29, no. 5 (October, 2006): 687.

Morales, Pamilla C. “Lesch-Nyhan Syndrome.” In Handbook of Neurodevelopmental and Genetic Disorders in Children, edited by Sam Goldstein and Cecil R. Reynolds. New York: Guilford Press, 1999.

Neychev, V. K., and H. A. Jinnah. “Sudden Death in Lesch-Nyhan Disease.” Developmental Medicine and Child Neurology 48, no. 11 (November, 2006): 923-926.

Schroeder, Stephan R., Mary Lou Oster-Granite, and Travis Thompson, eds. Self-Injurious Behavior: Gene-Brain-Behavior Relationships. Washington, D.C.: American Psychological Association, 2002.

Visser, Jasper E. “Lesch-Nyhan Syndrome.” In Handbook of Neurodevelopmental and Genetic Disorders in Adults, edited by Sam Goldstein and Cecil R. Reynolds. New York: Guilford Press, 2005.